Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 21 for “"Targeted protein degradation"”.
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Harnessing the Anaphase-Promoting Complex for Targeted Protein Degradation
Targeted protein degradation (TPD) is rapidly becoming a prevalent modality of therapeutics development due to its event-driven pharmacology that overcomes some major limitations of conventional small molecule inhibitors. One of the paradigms of TPD involves co-opting components of the …
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Construction and Biological Characterisation of Custom Engineered Protein Degradation Tools.
… inhibition approaches is Aurora A (AurA). Degradation rather than inhibition of AurA should be able to block non-catalytic functions that cannot be inhibited. Event-driven pharmacology can be effected using bifunctional constructs to recruit the cell’s degradation machinery to target …
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Targeting Cyclin T1 in Cancer
[Restricted]
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Cellular Determinants Of AURKA Degradation By Small Molecule Proteolysis-Targeting Chimeras
… signalling through advancing therapeutic targeted protein degradation (TPD) strategies and generating tools to explore the ubiquitin landscape. However, the cellular factors that modulate PROTAC activity, such as substrate characteristics and their interaction with components of the …
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Characterization of SCF Ubiquitin-Ligase Subunits in Arabidopsis
… of individual ASK:YFP auto-fluorescent fusion proteins expressed in vivo, as well as the in planta assessment of individual ASK-F-box protein interactions using BiFC. The results indicated significant functional divergence of steadystate transcript abundance and protein-protein interaction …
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Structural Insights into TRIM21 Ubiquitination Mechanisms
The attachment of ubiquitin (Ub) to proteins is one of the most abundant and versatile of all posttranslational modifications and affects outcomes in essentially all physiological processes. During ubiquitination, RING E3 ligases direct E2 Ub-conjugating enzymes to substrates to catalyze their …
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Structural Principles of Substrate Recognition and Unfolding by the ClpAP and ClpXP AAA+ Proteases
Protein degradation is a key regulatory mechanism that controls protein homeostasis in all cells. Found in all domains of life, proteases of the AAA+ (ATPases associated with diverse cellular activities) superfamily perform targeted protein degradation of specific substrates. All AAA+ proteases …
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Age related memory loss and the role of the ubiquitin proteasome system
… challenges, such as the accumulation of damaged proteins. The ubiquitin-proteasome system (UPS), responsible for breaking down damaged proteins, exhibits dysfunction in neurodegenerative disorders like Alzheimer's disease or dementia. While we acknowledge that proteasome function declines with …
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Targeting Transcription Factors in Neuroblastoma: Development of Aurora Kinase A/N-Myc Degraders and ID2 Chemical Probes
… modulators of TFs in neuroblastoma using targeted protein degradation. N-Myc overexpression is the most frequent driver in neuroblastoma. Unique features of N-Myc biology offer innovative approaches for developing chemical modulators of this oncogenic TF. For example, N-Myc is stabilized …
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Modulation of BAZ2 Proteins as a Potential Therapeutic Strategy in Cancer and Neurological Disorders
The complex landscape behind protein homeostasis involves a highly sophisticated system devoted to maintaining cellular balance and preventing dysfunction. In this context, the cellular machinery acts as a quality control mechanism, rapidly identifying and eliminating proteins that could impair …
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Mechanisms of TRIM21-directed intracellular degradation
… which catalyzes the formation of polymers of the protein ubiquitin around target substrates. When viruses coated in non-neutralizing antibodies escape into the cytosol, TRIM21 binds and decorates the complex with these polyubiquitin chains. Polyubiquitin is a highly-conserved protein post- …
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Selective Degradation of Aggregated Tau Protein Via Vectored Nanobody-TRIM21 RING Fusion Constructs
The accumulation of intraneuronal aggregated tau protein underlies many common neurodegenerative diseases and is a key target in therapeutic development. Whilst promising in pre-clinical models, tau targeting antibodies have performed poorly in clinical trials, potentially due to low target …
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Small-molecule approaches to interrogate the druggability of the VHL E3 Cullin RING Ubiquitin Ligase
Protein-protein interactions (PPIs) are prevalent in Nature and so are attractive targets for chemical biology and drug discovery. Modulating PPIs is challenging because of the nature of their interacting surfaces. Nevertheless, recent progress has led to the discovery of small molecule modulators …
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A study of novel tools to measure and perturb Aurora Kinase A protein stability
… classes in biology, we have been taught that proteins are the ‘molecular machinery’ of the cell, and that they carry out the cellular functions within the cell. At a top-down level, the amount of proteins present within a cell is a balance between its synthesis and degradation, the dynamic …
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Designed bifunctional proteins for induced degradation of androgen receptor in prostate cancer
… consensus-designed tetratricopeptide repeat proteins (CTPRs) were deployed as artificial modular scaffolds, onto which AR- and E3 ligase-binding moieties were grafted to induce AR ubiquitination and degradation. As the degraders bind AR through protein-protein interactions, we can effectively …
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Proteolysis-targeting chimeras as a novel strategy for targeting epigenetic mechanisms in Plasmodium falciparum parasites
… that bind to the active site of essential target proteins, thereby killing the causative organism, Plasmodium falciparum. However, such active site-dependent inhibitors face the major challenge of resistance development. We therefore proposed the use of Proteolysis-targeting chimeras (PROTACs) …
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Induced Degradation of G-Protein-Coupled Receptors Through Proteolysis Targeting Chimeras
<p>G protein-coupled receptors (GPCRs) are a family of heptahelical transmembrane proteins that can modulate various cellular signaling pathways and therefore are attractive drug targets. Despite high mutational rates of GPCRs in cancer there are few oncology FDA-approved anti-GPCR drugs, leaving a …
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The Design, Synthesis and in vitro Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Degradation of Protein Arginine Methyltransferase 1
Protein arginine methyltransferase 1 (PRMT1) is a protein responsible for the asymmetric dimethylation of arginine. PRMT1 is upregulated in a wide range of cancers and the reduction of PRMT1 activity reduces cell proliferation and tumour growth in cell and animal models of cancer. A reduction in …
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Targeting Protein Degradation to Uncover Novel Oncoprotein Drivers of Acute Leukemia
… survival of 30–40%. Small molecule induced protein degradation is a novel strategy that can be applied to currently undruggable targets and oncoproteins. In this paradigm, small molecule degraders (either Proteolysis Targeting Chimera (PROTAC) or Molecular Glue (MG)) redirect the cell’s …
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